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https://www.readbyqxmd.com/read/29791011/a-pharmacokinetic-and-pharmacogenetic-analysis-of-osteosarcoma-patients-treated-with-high-dose-methotrexate-data-from-the-os2006-sarcoma-09-trial
#1
Gabrielle Lui, Jean-Marc Treluyer, Brice Fresneau, Sophie Piperno-Neumann, Nathalie Gaspar, Nadège Corradini, Jean-Claude Gentet, Perrine Marec Berard, Valérie Laurence, Pascale Schneider, Natacha Entz-Werle, Hélène Pacquement, Frédéric Millot, Sophie Taque, Claire Freycon, Cyril Lervat, Marie Cécile Le Deley, Céline Mahier Ait Oukhatar, Laurence Brugieres, Gwénaël Le Teuff, Naïm Bouazza
Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials...
May 23, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29788329/pharmacokinetic-and-pharmacodynamic-properties-of-metronidazole-in-pediatric-patients-with-acute-appendicitis-a-prospective-study
#2
Jason Child, Xinhui Chen, Rakesh D Mistry, Stig Somme, Christine MacBrayne, Peter L Anderson, Ronald N Jones, Sarah K Parker
Background: Metronidazole is traditionally dosed every 6-8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis...
May 16, 2018: Journal of the Pediatric Infectious Diseases Society
https://www.readbyqxmd.com/read/29785089/schisandrin-b-ameliorated-chondrocytes-inflammation-and-osteoarthritis-via-suppression-of-nf-%C3%AE%C2%BAb-and-mapk-signal-pathways
#3
Jisheng Ran, Chiyuan Ma, Kai Xu, Langhai Xu, Yuzhe He, Safwat Adel Abdo Moqbel, Pengfei Hu, Lifeng Jiang, Weiping Chen, Jiapeng Bao, Yan Xiong, Lidong Wu
Introduction: Osteoarthritis (OA) is the most prevalent joint disorder in the elderly population, and inflammatory mediators like IL-1β were thought to play central roles in its development. Schisandrin B, the main active component derived from Schisandra chinensis , exhibited anti-oxidative and antiinflammatory properties. Methods: In the present study, the protective effect and the underlying mechanism of Schisan-drin B on OA was investigated in vivo and in vitro...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29782406/population-pharmacokinetics-and-pharmacodynamics-of-dexmedetomidine-in-children-undergoing-ambulatory-surgery
#4
María-Gabriela Pérez-Guillé, Alejandra Toledo-López, Liliana Rivera-Espinosa, Radames Alemon-Medina, Chiharu Murata, Ismael Lares-Asseff, Juan Luis Chávez-Pacheco, Josefina Gómez-Garduño, Ana-Lilia Zamora Gutiérrez, Claudia Orozco-Galicia, Karina Ramírez-Morales, Gustavo Lugo-Goytia
BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures...
May 17, 2018: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/29777502/oxi1-kinase-plays-a-key-role-in-resistance-of-arabidopsis-towards-aphids-myzus-persicae
#5
Tahsin Shoala, Martin G Edwards, Marc R Knight, Angharad M R Gatehouse
Plants have co-evolved with a diverse array of pathogens and insect herbivores and so have evolved an extensive repertoire of constitutive and induced defence mechanisms activated through complex signalling pathways. OXI1 kinase is required for activation of mitogen-activated protein kinases (MAPKs) and is an essential part of the signal transduction pathway linking oxidative burst signals to diverse downstream responses. Furthermore, changes in the levels of OXI1 appear to be crucial for appropriate signalling...
May 17, 2018: Transgenic Research
https://www.readbyqxmd.com/read/29776710/pharmacokinetics-pharmacodynamics-computer-decision-support-technologies-and-antimicrobial-stewardship-the-compass-and-rudder
#6
REVIEW
Robert C Owens, Catharine C Bulik, David R Andes
The first guidelines for conducting antimicrobial stewardship in the hospitalized setting were published in 2007. These guidelines recommend that stewardship programs employ the science of pharmacokinetics-pharmacodynamics (PK-PD) as well as adopting computerized decision support technologies when possible. The United States Food and Drug Administration have adopted PK-PD as a cornerstone in the evaluation of antimicrobial agents during clinical development. The core principles of PK-PD center around describing the relationship between drug exposure indexed to the susceptibility of the infecting bacterial pathogen and patient response...
April 13, 2018: Diagnostic Microbiology and Infectious Disease
https://www.readbyqxmd.com/read/29776017/pharmacokinetics-and-c-reactive-protein-modelling-of-anti-il-6-antibody-pf-04236921-in-healthy-volunteers-and-patients-with-autoimmune-disease
#7
Cheryl Li, Satoshi Shoji, Jean Beebe
AIMS: The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-IL-6 monoclonal antibody, and its pharmacokinetics/pharmacodynamics (PK/PD) relationship on serum C-Reactive Protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Crohn's disease (CD) METHODS: Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from 2 phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study, and a Phase 2 SLE study were included...
May 18, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29773888/antitumor-effect-of-axitinib-combined-with-dopamine-and-pk-pd-modeling-in-the-treatment-of-human-breast-cancer-xenograft
#8
Yuan-Heng Ma, Si-Yuan Wang, Yu-Peng Ren, Jian Li, Ting-Jie Guo, Wei Lu, Tian-Yan Zhou
Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA...
May 17, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29771285/increased-dolutegravir-peak-concentrations-in-people-living-with-hiv-aged-60-and-over-and-analysis-of-sleep-quality-and-cognition
#9
Emilie R Elliot, Xinzhu Wang, Suveer Singh, Bryony Simmons, Jaime H Vera, Robert F Miller, Colin Fitzpatrick, Graeme Moyle, Myra McClure, Marta Boffito
Background: Demographic data show an increasingly aging HIV population worldwide. Recent concerns over dolutegravir-related neuropsychiatric toxicity have emerged, particularly amongst older HIV patients. We describe the pharmacokinetics (PK) of dolutegravir (DTG) 50mg once daily in people living with HIV (PLWH) aged 60 and older. Additionally, to address the call for prospective neuropsychiatric toxicodynamic data, we evaluate changes in sleep quality and cognitive function after switching to abacavir (ABC)/lamivudine (3TC)/DTG, over 6 months in this population...
May 16, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29770901/factors-impacting-unbound-vancomycin-concentrations-in-neonates-and-young-infants
#10
Anne Smits, Steven Pauwels, Matthijs Oyaert, Nele Peersman, Isabel Spriet, Veroniek Saegeman, Karel Allegaert
Vancomycin pharmacokinetic (PK) and pharmacodynamic (PD) data in neonates are based on total concentrations. However, only unbound vancomycin is pharmacologically active. The objective was to determine vancomycin protein binding and the covariates impacting unbound vancomycin concentration in neonates and young infants. In neonates and young infants to whom vancomycin was administered intermittently for medical indications, total and unbound vancomycin plasma concentrations were determined using LC-MS/MS. Sampling occurred randomly during vancomycin exposure, covering a broad range of concentrations...
May 16, 2018: European Journal of Clinical Microbiology & Infectious Diseases
https://www.readbyqxmd.com/read/29769340/the-htlv-1-basic-leucine-zipper-factor-hbz-attenuates-repair-of-double-stranded-dna-breaks-via-non-homologous-end-joining-nhej
#11
A W Rushing, K Hoang, N Polakowski, I Lemasson
Adult T-cell leukemia (ATL) is a fatal malignancy of CD4+ T-cells infected with human T-cell leukemia virus type I (HTLV-1). ATL cells often exhibit random gross chromosomal rearrangements that are associated with the induction and improper repair of double-stranded DNA breaks (DSBs). The viral oncoprotein Tax has been reported to impair DSB repair, but is not shown to be consistently expressed throughout all phases of infection. The viral oncoprotein HTLV-1 basic leucine zipper factor (HBZ) is consistently expressed prior to and throughout disease progression, but it is unclear whether it also influences DSB repair...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29768717/pharmacokinetics-and-target-attainment-of-ceftobiprole-in-asian-and-non-asian-subjects
#12
A E Muller, N Punt, M Engelhardt, A H Schmitt-Hoffmann, J W Mouton
Ceftobiprole is a broad-spectrum cephalosporin. The objective of this study was to test the hypothesis that the pharmacokinetics (PK) and exposure of ceftobiprole in Asian subjects are similar to those in non-Asian subjects. Three approaches were followed. The first compared the individual PK estimates between the 2 subgroups derived from a population PK model previously built. Next, it was determined whether "Asian subject" was a significant covariate. Finally, a pharmacodynamic analysis was performed by comparing measures of exposure and target attainment...
May 16, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29762386/exposure-response-analysis-of-micafungin-in-neonatal-candidiasis-pooled-analysis-of-two-clinical-trials
#13
Laura L Kovanda, Thomas J Walsh, Daniel K Benjamin, Antonio Arrieta, David A Kaufman, P Brian Smith, Paolo Manzoni, Amit V Desai, Atsunori Kaibara, Peter L Bonate, William W Hope
BACKGROUND: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK)-pharmacodynamic (PD) bridging studies. However, little is known about the how these PK-PD data translate clinically. METHODS: Micafungin plasma concentrations from infants were used to construct a population PK model using Pmetrics software...
June 2018: Pediatric Infectious Disease Journal
https://www.readbyqxmd.com/read/29761906/the-pharmacokinetics-of-cytarabine-administered-subcutaneously-combined-with-prednisone-in-dogs-with-meningoencephalomyelitis-of-unknown-etiology
#14
B Pastina, P J Early, R L Bergman, J Nettifee, A Maller, K Y Bray, R J Waldron, A M Castel, K R Munana, M G Papich, K M Messenger
The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg-1 day-1 ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME)...
May 15, 2018: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29760144/personalizing-polymyxin-b-dosing-using-an-adaptive-feedback-control-algorithm
#15
Elizabeth A Lakota, Cornelia B Landersdorfer, Roger L Nation, Jian Li, Keith S Kaye, Gauri G Rao, Alan Forrest
Polymyxin B is used as an antibiotic of last resort for patients with multidrug-resistant Gram-negative bacterial infections; however, it carries a significant risk of nephrotoxicity. Herein we present a polymyxin B therapeutic window based on target area under the concentration-time curve (AUC) values and an adaptive feedback control algorithm (algorithm) which allows for the personalization of polymyxin B dosing. The upper bound of this therapeutic window was determined through a pharmacometric meta-analysis of polymyxin B nephrotoxicity data, and the lower bound was derived from murine thigh-infection pharmacokinetic/pharmacodynamic studies...
May 14, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29758263/page4-and-conformational-switching-insights-from-molecular-dynamics-simulations-and-implications-for-prostate-cancer
#16
Xingcheng Lin, Susmita Roy, Mohit Kumar Jolly, Federico Bocci, Nicholas P Schafer, Min-Yeh Tsai, Yihong Chen, Yanan He, Alexander Grishaev, Keith Weninger, John Orban, Prakash Kulkarni, Govindan Rangarajan, Herbert Levine, José N Onuchic
Prostate-Associated Gene 4 (PAGE4) is an intrinsically disordered protein (IDP) implicated in prostate cancer. The stress-response kinase Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates two residues in PAGE4, serine 9 and threonine 51. Phosphorylation of these two residues facilitates the interaction of PAGE4 with Activator Protein-1 (AP-1) transcription factor complex to potentiate AP-1's activity. In contrast, hyperphosphorylation of PAGE4 by CDC-Like Kinase 2 (CLK2) attenuates this interaction with AP-1...
May 11, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29757380/simultaneous-population-pharmacokinetic-modelling-of-plasma-and-intracellular-pbmc-miltefosine-concentrations-in-new-world-cutaneous-leishmaniasis-and-exploration-of-exposure-response-relationships
#17
Anke E Kip, María Del Mar Castro, Maria Adelaida Gomez, Alexandra Cossio, Jan H M Schellens, Jos H Beijnen, Nancy Gore Saravia, Thomas P C Dorlo
Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1...
May 10, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29755998/application-of-a-pharmacokinetic-model-of-metformin-clearance-in-a-population-with-acute-myeloid-leukemia
#18
Alice C Ceacareanu, Geoffrey W Brown, Hoda A Moussa, Zachary A P Wintrob
Objective: We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). Methods: All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003-December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability...
January 2018: Journal of Research in Pharmacy Practice
https://www.readbyqxmd.com/read/29755474/exercise-increases-insulin-sensitivity-and-skeletal-muscle-ampk-expression-in-systemic-lupus-erythematosus-a-randomized-controlled-trial
#19
Fabiana B Benatti, Cíntia N H Miyake, Wagner S Dantas, Vanessa O Zambelli, Samuel K Shinjo, Rosa M R Pereira, Maria Elizabeth R Silva, Ana Lúcia Sá-Pinto, Eduardo Borba, Eloisa Bonfá, Bruno Gualano
Systemic lupus erythematosus (SLE) patients may show increased insulin resistance (IR) when compared with their healthy peers. Exercise training has been shown to improve insulin sensitivity in other insulin-resistant populations, but it has never been tested in SLE. Therefore, the aim of the present study was to assess the efficacy of a moderate-intensity exercise training program on insulin sensitivity and potential underlying mechanisms in SLE patients with mild/inactive disease. A 12-week, randomized controlled trial was conducted...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29753686/pharmacological-inhibition-of-the-mitochondrial-nadph-oxidase-4-pkc%C3%AE-gal-3-pathway-reduces-left-ventricular-fibrosis-following-myocardial-infarction
#20
Maria Del Carmen Asensio-Lopez, Antonio Lax Perez, Maria Josefa Fernandez Del Palacio, Yassine Sassi, Roger J Hajjar, Domingo A Pascual-Figal
Although the initial reparative fibrosis after myocardial infarction (MI) is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental. Although metformin prevents adverse cardiac remodeling, as well as provides glycemic control, the underlying mechanisms remain poorly documented. This study describes the effect of mitochondrial NADPH oxidase 4 (mitoNox) and protein kinase C-alpha (PKCα) on the cardiac fibrosis and galectin 3 (Gal-3) expression...
April 23, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
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